Identification of an alternative ligand binding pocket in PPAR-? and its corelated selective agonist for promoting beige adipocyte differentiation

Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPAR-?) is a convenient and promising tactic for promoting beige adipocyte biogenesis to combat obesity-related metabolic disorders. However, thiazolidinediones (TZDs), the full agonist of PPAR-? exhibits severe side effects in animal model and clinical uses. Therefore, it is emerging to develop efficient and safe PPAR-? modulators for metabolic disease treatment. Here, by utilizing comprehensive methods, we report a previously unidentified ligand binding pocket (LBP) in PPAR-? and link it to beige adipocyte differentiation. Further virtual screening from 4097 natural compounds based on this novel LBP, we discover NJT-2, a terpenoid compound, can bind to PPAR-? induce co-activator recruitment and effectively activate PPAR-? mediated transcription of beige adipocyte program. Importantly, in mouse model, NJT-2 administration efficiently promotes beige adipocyte biogenesis and improve obesity-associated metabolic dysfunction with significant lower adverse effects than those observed in TZD. Our results not only provide an advanced molecular insight into the structural ligand binding details in PPARg, but also develop its linked selective and safe agonist for obesity treatment. Overall design: To explore the machanism of NJT-2 on promotion of biege cell, we performed the unbiased RNA-Seq to detailed described the metabolic phenotype of NJT-2 treated adipocytes.